Francisella tularensis is a gram-negative bacterium and one of the top-priority agents ("Class A") most likely to pose a potential risk to national security. Although much has been learned from a mouse model for which we used an attenuated strain of Francisella, Francisella tularensis live vaccine strain (LVS), little is known about how mice respond to virulent Francisella Type A strains (SCHU S4) with regard to immunity to inhalation exposure. There are few studies of virulent Type A strains of Francisella using mice and/or in mice exposed via inhalation challenge. The protective immune functions important for protection against intranasal or inhalation exposure to Francisella are still not completely understood or resolved. Studies in the mouse model of LVS have shown that cell-mediated immunity has an important function in host defense, but there is also new and recent evidence that antibodies play an important role in immunity. We recently developed a mouse model to assess development of protective immunity to intra-nasal challenge with virulent Francisella (SCHU S4). Mice challenged intra-nasally with a lethal dose of SCHU S4 and then treated with the drug levofloxacin were not only cured, but also developed protective immunity against intra-nasal re-challenge with SCHU S4. Importantly, we showed that serum from these immune mice protects naive mice from an intra-nasal infection with a lethal dose of SCHU S4. Our mouse model will allow a characterization of the immune functions important for such immunity and gives the opportunity to more fully investigate the role of antibody, coupled with CMI, in protection. The overall goal of this application is to test the hypothesis that mice infected intra- nasally with virulent Francisella tularensis (SCHU S4) and treated with levofloxacin develop a protective immunity that is mediated via both cell-mediated immunity and antibody. The specific aims that will test this hypothesis are: 1) To characterize the cell-mediated immune functions that are induced in mice challenged with virulent Francisella (SCHU S4) and treated with levofloxacin which leads to the generation of protective immunity, and 2) To characterize the role of cell-mediated immunity in the protection mediated by immune sera by using a passive transfer model. PUBLIC HEALTH RELEVANCE: Francisella tularensis, a bacterium that is one of the most infectious pathogens known, can be used as a bioweapon against the public via inhalation exposure. Unfortunately, little is currently known about how to protect the public against such a threat. This application will further our knowledge about this bacterium by developing an animal model for investigating future vaccine development